CINV occurs when the vomiting center located in the lateral reticular formation of the medulla oblongata receives a stimulus. The area postrema and the solitary nucleus of the medulla oblongata contain NK1 receptors, and the NK1 receptors are believed to be closely involved in vomiting.
Administration of an antineoplastic agent facilitates the serotonin secretion from the enterochromaffin (EC) cells in the digestive tract, and serotonin directly stimulates the vomiting center through 5-hydroxytryptamine3 (5-HT3) receptors in the digestive tract. Also, when serotonin stimulates the vomiting center through the chemoreceptor trigger zone (CTZ) located in the area postrema of the fourth ventricle, nausea and vomiting occur. Substance P, like serotonin, is found in the EC cells in the digestive tract, and its secretion is promoted by administration of an antineoplastic agent. Recently, it has been revealed that substance P induces vomiting through the NK1 receptors in the CTZ or by binding to the NK1 receptors in the central nervous system, and therefore NK1 receptors have been attracting attention as the target for developing antiemetic agents (Non-patent literature 1).
Aprepitant is the first selective NK1 receptor antagonist in the world which was approved as a preventive agent for nausea and vomiting associated with administration of antineoplastic agents. Regarding the mechanism of action of aprepitant, it is believed that aprepitant selectively inhibits the binding of substance P and the NK1 receptors in the central nervous system, which is one of the pathways that induce CINV, and thus prevents CINV. Aprepitant has been launched as a preventive agent for CINV (Non-patent literature 2).
It is known that aprepitant is metabolized by cytochrome P450 (CYP) 3A4. Also, aprepitant is known to have a dose-dependent inhibitory effect on CYP3A4, a CYP3A4-inducing effect and a CYP2C9-inducing effect. Accordingly, aprepitant may cause the drug-drug interactions with drugs that inhibit or induce CYP3A4 or with drugs that are metabolized by CYP3A4 or CYP2C9. For example, it is reported that the inhibitory effect of aprepitant on CYP3A4 sometimes inhibits the metabolism of dexamethasone and that the dose should be thus adjusted when dexamethasone is combined with aprepitant (Non-patent literature 3).
Therefore, when aprepitant is used, sufficient care should be directed to the drug-drug interactions based on the inhibitory effect of aprepitant on CYP3A4, a novel NK1 receptor antagonist is required as a preventive agent for CINV.
Compounds with an NK1 receptor antagonist activity are described in Patent literature 1 to 4.
However, in the above literatures, anything is neither described nor suggested about the NK1 receptor antagonist of the present invention.